Carboxylic acid derivatives, their production and use

ABSTRACT

Carboxylic acid derivatives of the formula I ##STR1## where the radicals have the meanings stated in the description, and the preparation of these agreements [sic] and their use as drugs are described.

This application is a 371 of PCT/EP97/01687, filed Apr. 4, 1997.

The present invention relates to novel carboxylic acid derivatives, to their preparation and to their use.

Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, "Endothelin" or "ET" signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature, 332, 1988, 411-415; FEBS Letters, 231, 1988, 440-444 und Biochem. Biophys. Res. Commun., 154, 1988, 868-875).

Increased or abnormal release of endothelin causes persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. It has been reported in the literature that elevated plasma levels of endothelin were found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension, 12, (1989), 79, J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868).

Accordingly, substances which specifically inhibit the binding of endothelin to the receptor ought also to antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.

We have found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors.

The invention relates to carboxylic derivatives of the formula I ##STR2## where R is tetrazole, nitrile, a group COOH or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:

R² hydrogen, hydroxyl, NH₂, NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, or CR² is linked to CR¹² as indicated below to form a 5- or 6-membered ring;

X nitrogen or CR¹² where R¹² is hydrogen or C₁₋₅ -alkyl, or CR¹² forms together with CR² or CR³ a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C₁₋₄ -alkyl groups and in which in each case one methylene group can be replaced by oxygen, sulfur, --NH or --NC₁₋₄ -alkyl;

Y nitrogen or methine;

R³ hydrogen, hydroxyl, NH₂, NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, --NH--O--C₁₋₄ -alkyl, C₁ -C₄ -alkylthio; or CR³ is linked to CR¹² as indicated above to form a 5- or 6-membered ring;

R⁴ and R⁵ (which can be identical or different):

phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino; or

phenyl or naphthyl, which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂ --, NH-- or N-alkyl group, or C₃ -C₇ -cycloalkyl;

R⁶ hydrogen, C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or C₃ -C₈ -cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C₁ -C₄ -alkoxy, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkynyloxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylcarbonyl, C₁ -C₄ -alkoxycarbonyl, C₃₋₈ -alkylcarbonylalkyl, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino, phenyl or phenoxy or phenyl, substituted one or more times, e.g. once to three times, by halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio;

phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino, dioxomethylene or dioxoethylene;

a five- or six-membered heteroaromatic system which contains one to three nitrogen atoms and/or one sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio;

Z sulfur or oxygen.

The compounds, and the intermediates for preparing them, such as II and IV, may have one or more asymmetrically substituted carbon atoms. Such compounds may be in the form of the pure enantiomers or pure diastereomers or a mixture thereof. The use of an enantiomerically pure compound as active substance is preferred.

The invention furthermore relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing endothelin receptor inhibitors.

Compounds of the general formula IV where Z is sulfur or oxygen can be prepared, also in enantiomerically pure form, as described in P 44 36 851.8. ##STR3##

Compounds according to the invention in which the substituents have the meanings stated under the general formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula IV in which the substituents have the stated meanings with compounds of the general formula V, ##STR4## where R¹³ is halogen or R¹⁴ --SO₂ --, where R¹⁴ can be C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl or phenyl. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, i.e. a base which deproteinates the intermediate IV, at a temperature in the range from room temperature to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitrites, such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, such as dimethyl sulfoxide and sulfolane.

Compounds of the formula V are known, and some of them can be bought, or they can be prepared in a conventional manner.

The base which can be used is an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, e.g. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium, or an alkali metal amide such as lithium diisopropylamide.

Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula I where R is COOH, and first converting the latter in a conventional way into an activated form, such as an acid halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HOR⁸. This reaction can be carried out in conventional solvents and often requires the addition of a base, in which case the abovementioned are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.

Moreover, compounds of the formula I can also be prepared by starting from salts of the corresponding carboxylic acids, i.e. from compounds of the formula I where R is a group COR¹ and R¹ is OM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R¹ --A where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or unsubstituted or halogen-, alkyl- or haloalkyl-substituted aryl- or alkylsulfonyl, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula R¹ --A with a reactive substituent A are known or can easily be obtained with general expert knowledge. This reaction can be carried out in conventional solvents and advantageously takes place with the addition of a base, in which case the abovementioned are suitable.

The radical R in formula I can be varied widely. R is, for example, a group ##STR5## where R¹ has the following meanings: a) hydrogen;

b) a succinylimidoxy group;

c) a 5-membered heteroaromatic system linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may then carry one or two halogen atoms or one or two C₁ -C₄ -alkyl or one or two C₁ -C₄ -alkoxy groups.

d) R¹ is furthermore a group ##STR6## where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R⁷ is C₁ -C₄ -alkyl, C₃ -C₇ -cycloalkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or unsubstituted or substituted phenyl which can be substituted by one or more, e.g. one to three, of the following radicals: halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, hydroxyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, mercapto, amino, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino;

R¹ is furthermore a radical OR⁸ where R⁸ is:

hydrogen, the cation of an alkali metal such as lithium, sodium, potassium, or the cation of an alkaline earth metal such as calcium, magnesium and barium or a physiologically tolerated organic ammonium ion such as tertiary C₁ -C₄ -alkylammonium or the ammonium ion;

C₃ -C₈ -cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl,

C₁ -C₈ -alkyl, in particular C₁ -C₄ -alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;

CH₂ -phenyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, hydroxyl, C₁ -C₄ -alkoxy, mercapto, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino, a C₃ -C₆ -alkenyl or C₃ -C₆ -alkynyl group, it being possible for this group in turn to carry one to five halogen atoms;

R⁸ can furthermore be a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, hydroxyl, C₁ -C₄ -alkoxy, mercapto, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino;

a 5-membered heteroaromatic system which is linked via a nitrogen atom and contains one to three nitrogen atoms and which can carry one or two halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, phenyl, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio. Particular mention may be made of 1-pyrazolyl,

3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloro-1-imidazolyl;

f) R¹ is furthermore a radical ##STR7## where R⁹ is: C₁ -C₄ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -cycloalkyl as mentioned above in particular, it being possible for these radicals to carry a C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio and/or a phenyl radical as mentioned above;

phenyl, unsubstituted or substituted, in particular as mentioned above;

g) R¹ is a radical ##STR8## where R⁹ has the abovementioned meaning; h) R¹ can furthermore be ##STR9## where R¹⁰ and R¹¹ can be identical or different and have the following meanings:

hydrogen, C₁ -C₇ -alkyl, C₃ -C₇ -cycloalkyl, C₃ -C₇ -alkenyl, C₃ -C₇ -alkynyl, benzyl, phenyl, unsubstituted or substituted, as described above,

or R¹⁰ and R¹¹ together form a C₄ -C₇ -alkylene chain which is closed to form a ring, is unsubstituted or substituted, e.g. substituted by C₁ -C₄ -alkyl, and may contain a heteroatom, e.g. oxygen, sulfur or nitrogen, such as --(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₆ --, --(CH₂)₇ --, --(CH₂)₂ --O--(CH₂)₂ --, --CH₂ --S--(CH₂)₂ --, --CH₂ --NH--(CH₂)₂ --, --(CH₂)₂ 13 N--(CH₂)₂ --.

With a view to the biological effect, preferred carboxylic acid derivatives of the general formula I, both as pure enantiomers and pure diastereomers or as mixtures thereof, are those where the substituents have the following meanings:

R² hydrogen, hydroxyl, N(C₁ -C₄ -alkyl)₂, the C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio groups and halogen atoms specifically mentioned for R¹, in particular chlorine, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, or CR² is linked to CR¹² as indicated below to form a 5- or 6-membered ring;

x nitrogen or CR¹², where

R¹² is hydrogen or alkyl, or CR¹² forms together with CR² or CR³ a 5- to 6-membered alkylene or alkenylene ring in which, in each case, a methylene group can be replaced by oxygen or sulfur, such as

--CH₂ --CH₂ --O--, --CH═CH--O--, --CH₂ --CH₂ --CH₂ --O--, --CH═CH--CH₂ O--, in particular hydrogen, --CH₂ --CH₂ --O--, --CH(CH₃)--CH(CH₃)--O--, --C(CH₃)═C(CH₃)--O--, --CH═C(CH₃)--O-- or --C(CH₃)═C(CH₃)--S;

Y nitrogen or methine;

R³ hydrogen, hydroxyl, N(C₁ -C₄ -alkyl)₂, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio groups and halogen atoms, in particular chlorine, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, or C--R³ is linked to C--R¹² as mentioned above to form a 5- or 6-membered ring;

R⁴ and R⁵, which may be identical or different, phenyl or naphthyl, each of which may be substituted by one or more, e.g. one to three, of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino, C₁ -C₄ -alkylcarbonyl, C₁ -C₄ -alkoxycarbonyl; phenyl or naphthyl, which may be connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N-alkyl group, or C₃ -C₇ cycloalkyl;

R⁶ C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or C₃ -C₈ -cycloalkyl as mentioned above in particular, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano,

C₁ -C₄ -alkoxy, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkynyloxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylcarbonyl, hydroxycarbonyl, C₁ -C₄ -alkoxycarbonyl, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino or unsubstituted or substituted phenyl or phenoxy, as mentioned above in particular;

phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino;

a five- or six-membered heteroaromatic system which contains one to three nitrogen atoms and/or one sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio, as mentioned for R⁴ in particular;

Z sulfur or oxygen.

Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those in which the substituents have the following meanings:

R² C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, trifluoromethyl or is linked to R¹² as mentioned below to form a 5- or 6-membered ring;

X nitrogen or CR¹², where

R¹² is hydrogen or alkyl, or CR¹² forms together with CR² or CR³ a 4- to 5-membered alkylene or alkenylene ring, e.g. --CH₂ --CH₂ --CH₂ -- or --CH═CH--CH₂ --, in which, in each case, one methylene group can be replaced by oxygen or sulfur, such as --CH₂ --CH₂ --O--, --CH═CH--O--,

--CH₂ --CH₂ --CH₂ --O--, --CH═CH--CH₂ O--, in particular hydrogen, --CH₂ --CH₂ --O--, --CH(CH₃)--CH(CH₃)--O--, --C(CH₃)═C(CH₃)--O--, --CH═C(CH₃)--O-- or --C(CH₃)═C(CH₃)--S;

Y nitrogen or methine;

R³ the C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio groups mentioned for R¹ or C--R³ is linked to C--R¹² as mentioned above to form a 5- or 6-membered ring;

R⁴ and R⁵ phenyl (identical or different), which may be substituted by one or more, e.g. one to three, of the following radicals: halogen, nitro, hydroxyl, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio or

R⁴ and R⁵ are phenyl groups which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N-alkyl group; or

R⁴ and R⁵ are C₃ -C₇ -cycloalkyl;

R⁶ C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl or C₃ -C₈ -cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, mercapto, caboxyl [sic], hydroxyl, nitro, cyano,

C₁ -C₄ -alkoxy, C₃ -C₆ -alkenyloxy, C₁ -C₄ -alkylthio;

phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -akylamino or C₁ -C₄ -dialkylamino;

a five- or six-membered heteroaromatic system which contains a nitrogen atom and/or a sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy and/or C₁ -C₄ -alkylthio;

Z sulfur or oxygen.

Examples of preferred compounds are listed in the following table.

                                      TABLE I                                      __________________________________________________________________________     [sic]                                                                             -                                                                             #STR10##                                                                        -                                                                           No.                                                                               R.sup.1                                                                           R.sup.4, R.sup.5                                                                      R.sup.6        R.sup.3                                                                           R.sup.2                                                                             X     Y Z                                  __________________________________________________________________________     I-1                                                                               OH phenyl methyl         OMe                                                                               OMe  N     N O                                    I-2 OH phenyl methyl OMe Me N N O                                              I-3 OH phenyl methyl Me OMe N N O                                              I-4 OH phenyl methyl ethyl Me N N O                                            I-5 OH phenyl methyl Me ethyl N N O                                            I-6 OH phenyl methyl Me Me N N O                                               I-7 OH phenyl methyl OMe SMe N N O                                             I-8 OH phenyl methyl OMe CF.sub.3 N N O                                        I-9 OH phenyl methyl OMe OMe N N S                                             I-10 OH phenyl methyl OMe Me N N S                                             I-11 OH phenyl methyl Me OMe N N S                                             I-12 OH phenyl methyl ethyl Me N N S                                           I-13 OH phenyl ethyl OMe OMe N N O                                             I-14 OH phenyl ethyl OMe Me N N O                                              I-15 OH phenyl ethyl Me OMe N N O                                              I-16 OH phenyl ethyl ethyl Me N N O                                            I-17 OH phenyl ethyl Me ethyl N N O                                            I-18 OH phenyl HO--CH.sub.2 --CH.sub.2 -- OMe OMe N N O                        I-19 OH phenyl HO--CH.sub.2 --CH.sub.2 -- OMe Me N N O                         I-20 OH phenyl HO--CH.sub.2 --CH.sub.2 -- Me OMe N N O                         I-21 OH phenyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me N N O                       I-22 OH phenyl HO--CH.sub.2 --CH.sub.2 -- Me ethyl N N O                       I-23 OH phenyl HO--CH.sub.2 --CH.sub.2 -- Me Me N N O                          I-24 OH phenyl HO--CH.sub.2 --CH.sub.2 -- OMe SMe N N O                        I-25 OH phenyl HO.sub.2 C--(CH.sub.2).sub.2 -- OMe OMe N N O                   I-26 OH phenyl HO.sub.2 C--(CH.sub.2).sub.2 -- OMe Me N N O                    I-27 OH phenyl HO.sub.2 C--(CH.sub.2).sub.2 -- Me OMe N N O                    I-28 OH phenyl HO.sub.2 C--(CH.sub.2).sub.2 -- ethyl Me N N O                  I-29 OH phenyl HO.sub.2 C--(CH.sub.2).sub.2 -- Me ethyl N N O                  I-30 OH phenyl HO.sub.2 C--(CH.sub.2).sub.2 -- Me Me N N O                     I-31 OH phenyl HO.sub.2 C--(CH.sub.2).sub.2 -- OMe SMe N N O                   I-32 OH phenyl HO.sub.2 C--CH.sub.2 -- OMe OMe N N O                           I-33 OH phenyl HO.sub.2 C--CH.sub.2 -- OMe Me N N O                            I-34 OH phenyl HO.sub.2 C--CH.sub.2 -- Me OMe N N O                            I-35 OH phenyl HO.sub.2 C--CH.sub.2 -- ethyl Me N N O                          I-36 OH phenyl HO.sub.2 C--CH.sub.2 -- Me ethyl N N O                          I-37 OH phenyl HO.sub.2 C--CH.sub.2 -- Me Me N N O                             I-38 OH phenyl HO.sub.2 C--CH.sub.2 -- OMe SMe N N O                           I-39 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- OMe OMe N N O                                                         I-40 OH phenyl HO--CH.sub.2                                                   --(CH--OH)--CH.sub.2 -- OMe                                                    Me N N O                             I-41 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- Me OMe N N O                                                          I-42 OH phenyl HO--CH.sub.2                                                   --(CH--OH)--CH.sub.2 -- ethyl                                                  Me N N O                             I-43 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- Me ethyl N N O                                                        I-44 OH phenyl HO--CH.sub.2                                                   --(CH--OH)--CH.sub.2 -- Me Me                                                  N N O                                I-45 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- OMe SMe N N O                                                         I-46 OH phenyl HO--CH.sub.2                                                   --(CH--OH)--CH.sub.2 -- OMe                                                    CF.sub.3 N N O                       I-47 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- OMe OMe N N S                                                         I-48 OH phenyl HO--CH.sub.2                                                   --(CH--OH)--CH.sub.2 -- OMe                                                    Me N N S                             I-49 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- Me OMe N N S                                                          I-50 OH phenyl HO--CH.sub.2                                                   --(CH--OH)--CH.sub.2 -- ethyl                                                  Me N N S                             I-51 OH phenyl HO--CH.sub.2 --CH.sub.2 -- OMe OMe N N S                        I-52 OH phenyl HO--CH.sub.2 --CH.sub.2 -- OMe Me N N S                         I-53 OH phenyl HO--CH.sub.2 --CH.sub.2 -- Me OMe N N S                         I-54 OH phenyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me N N S                       I-55 OH phenyl HO--(CH.sub.2).sub.3 -- OMe OMe N N O                           I-56 OH phenyl HO--(CH.sub.2).sub.3 -- OMe Me N N O                            I-57 OH phenyl HO--(CH.sub.2).sub.3 -- Me OMe N N O                            I-58 OH phenyl HO--(CH.sub.2).sub.3 -- ethyl Me N N O                          I-59 OH phenyl HO--(CH.sub.2).sub.3 -- Me ethyl N N O                          I-60 OH phenyl HO--(CH.sub.2).sub.3 -- Me Me N N O                             I-61 OH phenyl HO--(CH.sub.2).sub.3 -- OMe SMe N N O                           I-62 OH phenyl HO--(CH.sub.2).sub.3 -- OMe CF.sub.3 N N O                      I-63 OH phenyl HO--(CH.sub.2).sub.3 -- OMe OMe N N S                           I-64 OH phenyl HO--(CH.sub.2).sub.3 -- OMe Me N N S                            I-65 OH phenyl HO--(CH.sub.2).sub.3 -- Me OMe N N S                            I-66 OH phenyl HO--(CH.sub.2).sub.3 -- ethyl Me N N S                          I-67 OH phenyl n-propyl OMe OMe N N O                                          I-68 OH phenyl n-propyl OMe Me N N O                                           I-69 OH phenyl n-propyl Me OMe N N O                                           I-70 OH phenyl n-propyl ethyl Me N N O                                         I-71 OH phenyl n-propyl Me ethyl N N O                                         I-72 OH phenyl n-propyl Me Me N N O                                            I-73 OH phenyl n-propyl OMe SMe N N O                                          I-74 OH phenyl n-propyl OMe CF.sub.3 N N O                                     I-75 OH phenyl n-propyl OMe OMe N N S                                          I-76 OH phenyl n-propyl OMe Me N N S                                           I-77 OH phenyl n-propyl Me OMe N N S                                           I-78 OH phenyl n-propyl ethyl Me N N S                                         I-79 OH phenyl iso-propyl OMe OMe N N O                                        I-80 OH phenyl iso-propyl OMe Me N N O                                         I-81 OH phenyl iso-propyl Me OMe N N O                                         I-82 OH phenyl iso-propyl ethyl Me N N O                                       I-83 OH phenyl iso-propyl Me ethyl N N O                                       I-84 OH phenyl iso-propyl Me Me N N O                                          I-85 OH phenyl iso-propyl OMe SMe N N O                                        I-86 OH phenyl iso-propyl OMe CF.sub.3 N N O                                   I-87 OH phenyl iso-propyl OMe OMe N N S                                        I-88 OH phenyl iso-propyl OMe Me N N S                                         I-89 OH phenyl iso-propyl Me OMe N N S                                         I-90 OH phenyl iso-propyl ethyl Me N N S                                       I-91 OH phenyl methyl CF.sub.3 tert-Butyl N N O                                I-92 OH phenyl methyl CF.sub.3 OMe N N O                                       I-93 OH phenyl methyl SMe OMe N N O                                            I-94 OH phenyl methyl CF.sub.3 Me N N O                                        I-95 OH phenyl methyl Me CF.sub.3 N N O                                        I-96 OH phenyl benzyl OMe Me N N O                                             I-97 OH phenyl benzyl Me OMe N N O                                             I-98 OH phenyl benzyl ethyl Me N N O                                           I-99 OH phenyl benzyl Me ethyl N N O                                           I-100 OH phenyl benzyl Me Me N N O                                             I-101 OH phenyl benzyl OMe OMe N N O                                           I-102 OH phenyl phenyl OMe Me N N O                                            I-103 OH phenyl phenyl Me OMe N N O                                            I-104 OH phenyl phenyl ethyl Me N N O                                          I-105 OH phenyl phenyl Me ethyl N N O                                          I-106 OH phenyl phenyl Me Me N N O                                             I-107 OH phenyl phenyl OMe OMe N N O                                           I-108 OH phenyl 4-OMe-benzyl OMe Me N N O                                      I-109 OH phenyl 4-OMe-benzyl Me OMe N N O                                      I-110 OH phenyl 4-OMe-benzyl ethyl Me N N O                                    I-111 OH phenyl 4-OMe-benzyl Me ethyl N N O                                    I-112 OH phenyl 4-OMe-benzyl Me Me N N O                                       I-113 OH phenyl 4-OMe-benzyl OMe OMe N N O                                     I-114 OH phenyl 4-Cl-benzyl OMe Me N N O                                       I-115 OH phenyl 4-Cl-benzyl Me OMe N N O                                       I-116 OH phenyl 4-Cl-benzyl ethyl Me N N O                                     I-117 OH phenyl 4-Cl-benzyl Me ethyl N N O                                     I-118 OH phenyl 4-Cl-benzyl Me Me N N O                                        I-119 OH phenyl 4-Cl-benzyl OMe OMe N N O                                      I-120 OH cyclohexyl methyl OMe OMe N N O                                       I-121 OH cyclohexyl methyl OMe Me N N O                                        I-122 OH cyclohexyl methyl Me OMe N N O                                        I-123 OH cyclohexyl methyl ethyl Me N N O                                      I-124 OH cyclohexyl methyl Me ethyl N N O                                      I-125 OH cyclohexyl methyl Me CF.sub.3 N N O                                   I-126 OH cyclohexyl ethyl OMe Me N N O                                         I-127 OH cyclohexyl ethyl Me OMe N N O                                         I-128 OH cyclohexyl ethyl ethyl Me N N O                                       I-129 OH cyclohexyl ethyl OMe ethyl N N O                                      I-130 OH cyclohexyl HO--CH.sub.2 --CH.sub.2 -- OMe Me N N O                    I-131 OH cyclohexyl HO--CH.sub.2 --CH.sub.2 -- Me OMe N N O                    I-132 OH cyclohexyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me N N O                  I-133 OH cyclohexyl HO--CH.sub.2 --CH.sub.2 -- Me ethyl N N O                  I-134 OH cyclohexyl HO--CH.sub.2 --CH.sub.2 -- Me Me N N O                     I-135 OH 4-fluorophenyl methyl OMe OMe N N O                                   I-136 OH 4-fluorophenyl methyl OMe Me N N O                                    I-137 OH 4-fluorophenyl methyl Me OMe N N O                                    I-138 OH 4-fluorophenyl methyl ethyl Me N N O                                  I-139 OH 4-fluorophenyl methyl Me ethyl N N O                                  I-140 OH 4-fluorophenyl methyl Me CF.sub.3 N N O                               I-141 OH 4-fluorophenyl ethyl OMe Me N N O                                     I-142 OH 4-fluorophenyl ethyl Me OMe N N O                                     I-143 OH 4-fluorophenyl ethyl Me Et N N O                                      I-144 OH 4-fluorophenyl ethyl OMe ethyl N N O                                  I-145 OH 4-fluorophenyl HO--CH.sub.2 --CH.sub.2 -- OMe Me N N O                                                           I-146 OH 4-fluorophenyl                                                       HO--CH.sub.2 --CH.sub.2 -- Me                                                  OMe N N O                            I-147 OH 4-fluorophenyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me N N O                                                         I-148 OH 4-fluorophenyl                                                       HO--CH.sub.2 --CH.sub.2 -- Me                                                  ethyl N N O                          I-149 OH 4-fluorophenyl HO--CH.sub.2 --CH.sub.2 -- Me Me N N O                 I-150 OH 4-fluorophenyl HO--CH.sub.2 --CH.sub.2 -- OMe OMe N N O                                                          I-151 OH 4-chlorophenyl                                                       methyl OMe Me N N O                  I-152 OH 4-chlorophenyl methyl Me OMe N N O                                    I-153 OH 4-chlorophenyl methyl ethyl Me N N O                                  I-154 OH 4-chlorophenyl methyl Me ethyl N N O                                  I-155 QH 4-chlorophenyl methyl Me CF.sub.3 N N O                               I-156 OH 4-chlorophenyl ethyl OMe Me N N O                                     I-157 OH 4-chlorophenyl ethyl Me OMe N N O                                     I-158 OH 4-chlorophenyl ethyl Me Et N N O                                      I-159 OH 4-chlorophenyl ethyl OMe ethyl N N O                                  I-160 OH 4-chlorophenyl HO--CH.sub.2 --CH.sub.2 -- OMe Me N N O                                                           I-161 OH 4-chlorophenyl                                                       HO--CH.sub.2 --CH.sub.2 -- Me                                                  OMe N N O                            I-162 OH 4-chlorophenyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me N N O                                                         I-163 OH 4-chlorophenyl                                                       HO--CH.sub.2 --CH.sub.2 -- Me                                                  ethyl N N O                          I-164 OH 4-chlorophenyl HO--CH.sub.2 --CH.sub.2 -- Me Me N N O                 I-165 OH 4-methylphenyl methyl Me Me N N O                                   I-166                                                                             OH phenyl methyl         CH.sub.3                                                                          CH═CH--CH═CH--C                                                                   N O                                    I-167 OH phenyl methyl H CH═CH--CH═CH--C N O                         I-168                                                                             OH phenyl methyl         Me Me   CH    N O                                    I-169 OH phenyl methyl Me ethyl CH N O                                         I-170 OH phenyl methyl ethyl Me CH N O                                         I-171 OH phenyl methyl OMe Me CH N O                                         I-172                                                                             OH phenyl methyl         Me CH.sub.2 --CH.sub.2 --CH.sub.2 --C                                                        N O                                    I-173 OH phenyl methyl ethyl CH.sub.2 --CH.sub.2 --CH.sub.2 --C N O          I-174                                                                             OH phenyl methyl         CF.sub.3                                                                          Me   CH    N O                                    I-175 OH phenyl methyl CF.sub.3 ethyl CH N O                                 I-176                                                                             OH phenyl ethyl          CH.sub.3                                                                          CH═CH--CH═CH--C                                                                   N O                                    I-177 OH phenyl ethyl H CH═CH--CH═CH--C N O                          I-178                                                                             OH phenyl ethyl          Me Me   CH    N O                                    I-179 OH phenyl ethyl Me ethyl CH N O                                          I-180 OH phenyl ethyl ethyl Me CH N O                                          I-181 OH phenyl ethyl OMe Me CH N O                                          I-182                                                                             OH phenyl ethyl          Me CH.sub.2 --CH.sub.2 --CH.sub.2 --C                                                        N O                                    I-183 OH phenyl ethyl ethyl CH.sub.2 --CH.sub.2 --CH.sub.2 --C N O           I-184                                                                             OH phenyl ethyl          CF.sub.3                                                                          Me   CH    N O                                    I-185 OH phenyl ethyl CF.sub.3 ethyl CH N O                                  I-186                                                                             OH phenyl n-propyl       CH.sub.3                                                                          CH═CH--CH═CH--C                                                                   N O                                    I-187 OH phenyl n-propyl H CH═CH--CH═CH--C N O                       I-188                                                                             OH phenyl n-propyl       Me Me   CH    N O                                    I-189 OH phenyl n-propyl Me ethyl CH N O                                       I-190 OH phenyl n-propyl ethyl Me CH N O                                       I-191 OH phenyl n-propyl OMe Me CH N O                                       I-192                                                                             OH phenyl n-propyl       Me CH.sub.2 --CH.sub.2 --CH.sub.2 --C                                                        N O                                    I-193 OH phenyl n-propyl ethyl CH.sub.2 --CH.sub.2 --CH.sub.2 --C N O        I-194                                                                             OH phenyl n-propyl       CF.sub.3                                                                          Me   CH    N O                                    I-195 OH phenyl n-propyl CF.sub.3 ethyl CH N O                               I-196                                                                             OH phenyl HO--CH.sub.2 --CH.sub.2 --                                                                    CH.sub.3                                                                          CH═CH--CH═CH--C                                                                   N O                                    I-197 OH phenyl HO--CH.sub.2 --CH.sub.2 -- H CH═CH--CH═CH--C N                                                   O                                  I-198                                                                             OH phenyl HO--CH.sub.2 --CH.sub.2 --                                                                    Me Me   CH    N O                                    I-199 OH phenyl HO--CH.sub.2 --CH.sub.2 -- Me ethyl CH N O                     I-200 OH phenyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me CH N O                     I-201 OH phenyl HO--CH.sub.2 --CH.sub.2 -- OMe Me CH N O                     I-202                                                                             OH phenyl HO--CH.sub.2 --CH.sub.2 --                                                                    Me CH.sub.2 --CH.sub.2 --CH.sub.2 --C                                                        N O                                    I-203 OH phenyl HO--CH.sub.2 --CH.sub.2 -- ethyl CH.sub.2 --CH.sub.2                                                     --CH.sub.2 --C N O                 I-204                                                                             OH phenyl HO--CH.sub.2 --CH.sub.2 --                                                                    CF.sub.3                                                                          Me   CH    N O                                    I-205 OH phenyl HO--CH.sub.2 --CH.sub.2 -- CF.sub.3 ethyl CH N O             I-206                                                                             OH phenyl HOOC--CH.sub.2 --CH.sub.2 --                                                                  CH.sub.3                                                                          CH═CH--CH═CH--C                                                                   N O                                    I-207 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- H CH═CH--CH═CH--C                                                   N O                                I-208                                                                             OH phenyl HOOC--CH.sub.2 --CH.sub.2 --                                                                  Me Me   CH    N O                                    I-209 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- Me ethyl CH N O                   I-210 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- ethyl Me CH N O                   I-211 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- OMe Me CH N O                   I-212                                                                             OH phenyl HOOC--CH.sub.2 --CH.sub.2 --                                                                  Me CH.sub.2 --CH.sub.2 --CH.sub.2 --C                                                        N O                                    I-213 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- ethyl CH.sub.2 --CH.sub.2                                                   --CH.sub.2 --C N O                 I-214                                                                             OH phenyl HOOC--CH.sub.2 --CH.sub.2 --                                                                  CF.sub.3                                                                          Me   CH    N O                                    I-215 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- CF.sub.3 ethyl CH N O                                                        I-216 OH phenyl HO--CH.sub.2                                                  --(CH--OH)--CH.sub.2 -- Me Me                                                  CH N O                               I-217 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- Me ethyl CH N O                                                      I-218 OH phenyl HO--CH.sub.2                                                  --(CH--OH)--CH.sub.2 -- ethyl                                                  Me CH N O                            I-219 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- OMe Me CH N O                                                        t-220 OH phenyl iso-propyl                                                    Me Me CH N O                         I-221 OH phenyl iso-propyl Me ethyl CH N O                                     I-222 OH phenyl iso-propyl ethyl Me CH N O                                     I-223 OH phenyl iso-propyl OMe Me CH N O                                       I-224 OH phenyl methyl Me Me CH N S                                            I-225 OH phenyl methyl Me ethyl CH N S                                         I-226 OH phenyl methyl ethyl Me CH N S                                         I-227 OH phenyl methyl OMe Me CH N S                                           I-228 OH 4-fluorophenyl methyl Me Me CH N O                                    I-229 OH 4-fluorophenyl methyl Me ethyl CH N O                                 I-230 OH 4-fluorophenyl methyl ethyl Me CH N O                                 I-231 OH 4-fluorophenyl methyl OMe Me CH N O                                   I-232 OH 4-fluorophenyl methyl CF.sub.3 Me CH N O                              I-233 OH 4-fluorophenyl methyl CF.sub.3 ethyl CH N O                           I-234 OH 4-fluorophenyl HO--CH.sub.2 --CH.sub.2 -- Me Me CH N O                                                           I-235 OH 4-fluorophenyl                                                       HO--CH.sub.2 --CH.sub.2 -- Me                                                  ethyl CH N O                         I-236 OH 4-fluorophenyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me CH N O                                                        I-237 OH 4-fluorophenyl                                                       HO--CH.sub.2 --CH.sub.2 --                                                     OMe Me CH N O                        I-238 OH 4-chlorophenyl methyl Me Me CH N O                                    I-239 OH 4-chlorophenyl methyl Me ethyl CH N O                                 I-240 OH 4-chlorophenyl methyl ethyl Me CH N O                                 I-241 OH 4-chlorophenyl methyl OMe Me CH N O                                   I-242 OH 4-chlorophenyl methyl CF.sub.3 Me CH N O                              I-243 OH 4-chlorophenyl methyl CF.sub.3 ethyl CH N Q                           I-244 OH 4-chlorophenyl HO--CH.sub.2 --CH.sub.2 -- Me Me CH N O                                                           I-245 OH 4-chlorophenyl                                                       HO--CH.sub.2 --CH.sub.2 -- Me                                                  ethyl CH N O                         I-246 OH 4-chlorophenyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me CH N O                                                        I-247 OH 4-chlorophenyl                                                       HO--CH.sub.2 --CH.sub.2 --                                                     OMe Me CH N O                        I-248 OH phenyl ethyl Me Me N N O                                              I-249 OH phenyl ethyl OMe SMe N N O                                            I-250 OH phenyl ethyl OMe CF.sub.3 N N O                                       I-251 OH phenyl methyl OMe OMe N CH O                                          I-252 OH phenyl methyl OMe Me N CH O                                           I-253 OH phenyl methyl Me Me N CH O                                            I-254 OH phenyl methyl ethyl Me N CH O                                         I-255 OH phenyl methyl ethyl ethyl N CH O                                      I-256 OH phenyl methyl CF.sub.3 Me N CH O                                      I-257 OH phenyl methyl CF.sub.3 ethyl N CH O                                   I-258 OH phenyl methyl OMe CF.sub.3 N CH O                                     I-259 OH phenyl methyl OMe OMe N CH S                                          I-260 OH phenyl methyl OMe Me N CH S                                           I-261 OH phenyl methyl Me Me N CH S                                            I-262 OH phenyl methyl ethyl Me N CH S                                         I-263 OH phenyl ethyl OMe OMe N CH O                                           I-264 OH phenyl ethyl OMe Me N CH O                                            I-265 OH phenyl ethyl Me Me N CH O                                             I-266 OH phenyl ethyl ethyl Me N CH O                                          I-267 OH phenyl HO--CH.sub.2 --CH.sub.2 -- OMe OMe N CH O                      I-268 OH phenyl HO--CH.sub.2 --CH.sub.2 -- OMe Me N CH O                       I-269 OH phenyl HO--CH.sub.2 --CH.sub.2 -- Me Me N CH O                        I-270 OH phenyl HO--CH.sub.2 --CH.sub.2 -- ethyl Me N CH O                     I-271 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- OMe OMe N CH O                                                       I-272 OH phenyl HO--CH.sub.2                                                  --(CH--OH)--CH.sub.2 -- OMe                                                    Me N CH O                            I-273 OH phenyl HO--CH.sub.2 --(CH--OH)--CH.sub.2 -- Me Me N CH O                                                         I-274 OH phenyl HO--CH.sub.2                                                  --(CH--OH)--CH.sub.2 -- ethyl                                                  Me N CH O                            I-275 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- OMe OMe N CH O                    I-276 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- OMe Me N CH O                     I-277 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- Me Me N CH O                      I-278 OH phenyl HOOC--CH.sub.2 --CH.sub.2 -- ethyl Me N CH O                   I-279 OH phenyl propyl OMe OMe N CH O                                          I-280 OH phenyl propyl OMe Me N CH O                                           I-281 OH phenyl propyl Me Me N CH O                                            I-282 OH phenyl propyl ethyl Me N CH O                                         I-283 OH phenyl 4-OMe-benzyl OMe OMe N CH O                                    I-284 OH phenyl 4-OMe-benzyl OMe Me N CH O                                     I-285 OH phenyl 4-OMe-benzyl Me Me N CH O                                      I-286 OH phenyl 4-OMe-benzyl ethyl Me N CH O                                   I-287 OH 4-fluorophenyl methyl OMe OMe N CH O                                  I-288 OH 4-fluorophenyl methyl OMe Me N CH O                                   I-289 OH 4-fluorophenyl methyl Me Me N CH O                                    I-290 OH 4-fluorophenyl methyl ethyl Me N CH O                                 I-291 OH 4-fluorophenyl ethyl OMe OMe N CH O                                   I-292 OH 4-fluorophenyl ethyl OMe Me N CH O                                    I-293 OH 4-fluorophenyl ethyl Me Me N CH O                                     I-294 OH 4-fluorophenyl ethyl ethyl Me N CH O                                  I-295 OH 4-fluorophenyl HO--CH.sub.2 --CH.sub.2 -- OMe OMe N CH O                                                         I-296 OH 4-fluorophenyl                                                       HO--CH.sub.2 --CH.sub.2 --                                                     OMe Me N CH O                        I-297 OH 4-fluorophenyl HO--CH.sub.2 --CH.sub.2 -- Me Me N CH O                                                           I-298 OH 4-fluorophenyl                                                       HO--CH.sub.2 --CH.sub.2 --                                                     ethyl Me N CH O                      I-299 OH 4-chlorophenyl methyl OMe OMe N CH O                                  I-300 OH 4-chlorophenyl methyl OMe Me N CH O                                   I-301 OH 4-chlorophenyl methyl Me Me N CH O                                    I-302 OH 4-chlorophenyl methyl ethyl Me N CH O                                 I-303 OH 4-chlorophenyl ethyl OMe OMe N CH O                                   I-304 OH 4-chlorophenyl ethyl OMe Me N CH O                                    I-305 OH 4-chlorophenyl ethyl Me Me N CH O                                     I-306 OH 4-chlorophenyl ethyl ethyl Me N CH O                                  I-307 OH 4-chlorophenyl HO--CH.sub.2 --CH.sub.2 -- OMe OMe N CH O                                                         I-308 OH 4-chlorophenyl                                                       HO--CH.sub.2 --CH.sub.2 --                                                     OMe Me N CH O                        I-309 OH 4-chlorophenyl HO--CH.sub.2 --CH.sub.2 -- Me Me N CH O                                                           I-310 OH 4-chlorophenyl                                                       HO--CH.sub.2 --CH.sub.2 --                                                     ethyl Me N CH O                    __________________________________________________________________________

The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoidal hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, or hypertension or kidney failure caused by ischemia or intoxication, and of cancers, especially prostate cancer and skin cancer. The invention further relates to the combination of compounds of the formula I with inhibitors of the renin-angiotensin system (RAS). RAS inhibitors are disclosed in, for example, EP 634 175.

The combinations according to the invention are suitable for treating disorders for which compounds of the formula I also shows efficacy on their own, especially for treating hypertension and chronic heart failure.

The good effect of the compounds can be shown in the following tests:

Receptor Binding Studies

Cloned human ET_(A) receptor-expressing CHO cells and guinea pig cerebellar membranes with >60% ET_(B) compared with ET_(A) receptors were used for binding studies.

Membrane Preparation

The ET_(A) receptor-expressing CHO cells were grown in F₁₂ medium containing 10% fetal calf serum, 1% glutamine, 100 E/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization was then carried out with F₁₂ medium and the cells were collected by centrifugation at 300×g. To lyse the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 10⁷ cells/ml of lysis buffer at 4° C. for 30 min. The membranes were centrifuged at 20,000×g for 10 min, and the pellet was stored in liquid nitrogen.

Guinea pig cerebella were homogenized in a Potter-Elvejhem homogenizer and were obtained by differential centrifugation at 1,000×g for 10 min and repeated centrifugation of the supernatent at 20,000×g for 10 min.

Binding Assays

For the ET_(A) and ET_(B) receptor binding assay, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4 with 5 mM of MnCl₂, 40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of protein per assay mixture and incubated with 25 pM [125I ]-ET₁ (ET_(A) receptor assay) or 25 pM [125I]-RZ₃ (ET_(B) receptor assay) in the presence and absence of test substance. The nonspecific binding was determined with 10⁻⁷ M ET₁. After 30 min, filtration was carried out through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) to separate free and bound radioligands, and the filters were washed with ice-cold tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional in Vitro Assay System to Look for Endothelin Receptor (Subtype A) Antagonists

This assay system is a functional, cell-based assay for endothelin receptors. When certain cells are stimulated with endothelin 1 (ET1) they show an increase in the intracellular calcium concentration. This increase can be measured in intact cells loaded with calcium-sensitive dyes.

1-Fibroblasts which had been isolated from rats and in which an endogenous endothelin receptor of the A subtype had been detected were loaded with the fluorescent dye Fura 2-an as follows: after trypsinization, the cells were resuspended in buffer A (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl₂, 1 mM CaCl₂, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density of 2×10⁶ /ml and incubated with Fura 2-am (2 μM), Pluronics [sic] F-127 (0.04%) and DMSO (0.2%) at 37° C. in the dark for 30 min. The cells were then washed twice with buffer A and resuspended at 2×10⁶ /ml.

The fluorescence signal from 2×10⁵ cells per ml with Ex/Em 380/510 was recorded continuously at 30° C. The test substances and, after an incubation time of 3 min, ET1 were to the cells, the maximum change in the fluorescence was determined. The response of the cells to ET1 without previous addition of a test substance was used as control and was set equal to 100%.

Testing of ET Antagonists in Vivo

Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were cathetized.

In control animals, intravenous administration of 1 μg/kg ET1 led to a distinct rise in blood pressure which persisted for a lengthy period.

The test animals received an i.v. injection of the test compounds (1 ml/kg) 5 min before administration of ET1. To determine the ET-antagonistic properties, the rise in blood pressure in the test animals was compared with that in the control animals.

Endothelin-1 Induced "Sudden Death" in Mice

The principle of the test is the inhibition of the sudden heart death caused in mice by endothelin, which is probably induced by constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol/kg endothelin in a volume of 5 ml/kg of bodyweight results in death of the animals within a few minutes.

The lethal endothelin-1 dose is checked in each case on a small group of animals. If the test substance is administered intravenously, the endothelin-1 injection which was lethal in the reference group usually takes place 5 min thereafter. With other modes of administration, the times before administration are extended, where appropriate up to several hours.

The survival rate is recorded, and effective doses which protect 50% of the animals (ED 50) from endothelin-induced heart death for 24 h or longer are determined.

Function Test on Vessels for Endothelin Receptor Antagonists

Segments of rabbit aorta are, after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37° C. and pH 7.3-7.4, first induced to contract with K⁺. After washing out, an endothelin dose-effect plot up to the maximum is constructed.

Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before starting the endothelin dose-effect plot. The effects of the endothelin are calculated as % of the K³⁰ -induced contraction. Effective endothelin antagonists result in a shift to the right in the endothelin dose-effect plot.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. The daily dose of active substance is, as a rule, about 0.5 to 50 mg/kg of bodyweight on oral administration and about 0.1-10 mg/kg of bodyweight on parenteral administration.

The novel compounds can be used in conventional solid or liquid pharmaceutical forms, e.g. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The forms obtained in this way normally contain from 0.1 to 90% by weight of active substance.

Synthesis Examples

EXAMPLE 1

Methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 50 ml of absolute methanol, and, at 0° C., 0.1 ml of boron trifluoride etherate was added. The mixture was stirred at 0° C. for 2 h and at room temperature for a further 12 h. The solvent was removed by distillation, the residue was taken up in ethyl acetate, and the solution was washed with sodium bicarbonate solution and water and dried over magnesium sulfate. After removal of the solvent by distillation, 5.5 g (88%) of a pale yellow oil remained.

EXAMPLE 2

Methyl 2-(2,6-dimethoxy-4-pyrimidyloxy)-3-methoxy-3,3-diphenyl-propionate

1.15 g (4 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate were dissolved in 10 ml of dimethylformamide, and 276 mg (2 mmol) of potassium carbonate were added. Then 524 mg (3 mmol) of 2,6-dimethoxy-4-chloropyrimidine were added, and the mixture was stirred at 100° C. for 6 hours. It was then cautiously hydrolyzed with 10 ml of water, the pH was adjusted to 5 with citric acid and, after extraction with ethyl acetate, the organic phase was washed with water then dried over magnesium sulfate, and the solvent was removed by distillation. The oily residue (1.9 g) was chromatographed on silica gel, resulting in 617 mg of a slightly impure oil.

EXAMPLE 3

2-(2,6-Dimethoxy-4-pyrimidinyloxy)-3-methoxy-3,3-diphenyl-propionic acid

550 mg (1.3 mmol) of methyl 2-(2,6-dimethoxy-4-pyrimidinyl-oxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 5 ml of dioxane, 2.6 ml of 1N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and was extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residual foam (425 mg) was purified by MPLC, resulting in 205 mg (40%) of product as foam.

EXAMPLE 4

Methyl 2-(4-methyl-2-quinolinyloxy)-3-methoxy-3,3-diphenyl-propionate

5.7 g (20 mmol) of Methyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate were dissolved in 90 ml of dimethylformamide, and 0.98 g (22 mmol) of sodium hydride (55% in oil) was added. After stirring for 15 minutes, 3.9 g (22 mmol) of 2-chloro-4-methylquinoline were added. The dark red solution was stirred at room temperature overnight, then cautiously hydrolyzed with 20 ml of water and subsequently extracted with ethyl acetate. The organic phase was washed with water, and dried over magnesium sulfate, and the solvent was removed by distillation. The residue (8.1 g) was then chromatographed on silica gel, resulting in 2.6 g of impure product as oil.

EXAMPLE 5

2-(4-Methyl-2-quinolinyloxy)-3-methoxy-3,3-diphenylpropionic acid

1.8 g (4.2 mmol) of methyl 2-(4-methyl-2-quinolinyloxy)-3-meth-oxy-3,3-diphenylpropionate were dissolved in 25 ml of dioxane, 8.4 ml of 1N KOH solution were added, and the mixture was stirred at 60° C. for 20 hours. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester and impurities. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and was extracted with ethyl acetate. Drying over magnesium sulfate and removal of the solvent by distillation resulted in 1.0 g of a foam. This was dissolved in a little ethyl acetate and left to stand at room temperature overnight, during which 265 mg of the product separated out as white crystals. Repetition of this procedure with the mother liquor afforded a further 166 mg of the product.

Total yield: 431 mg≐25%

Melting point: 131-133° C.

MS: M⁺ =413

EXAMPLE 6

Benzyl 2-(2-tert-butyl-6-trifluoromethyl-4-pyrimidinyloxy) -3-methoxy-3,3-diphenylpropionate

2.0 g (5.5 mmol) of benzyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate (see P44 36 851.8) were dissolved in 20 ml of dimethylformamide, and 0.76 g (5.5 mmol) of potassium carbonate was added. Then 1.32 g (5.5 mmol) of 2-tert-butyl-6-trifluoro-methyl-4-chloropyrimidine were added, and the mixture was stirred at room temperature overnight and then at 100° C. for 5 hours. To complete the reaction, a further 0.5 g of the pyrimidine and 0.5 g of NaH were added, and the mixture was stirred at 60° C. for a further 6 hours. Finally, it was poured into ice-water and extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed by distillation. The oily residue (3.5 g) crystallized in n-heptane/ethyl acetate (5%). The precipitate was filtered off with suction and dried.

Yield: 1.6 g≐52%

MS: M⁺ =564

EXAMPLE 7

2-(2-tert-Butyl-6-trifluoromethyl-4-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionic acid

2.0 g (5.5 mmol) of benzyl 2-(2-tert-butyl-6-trifluoro-methyl-4-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 250 ml of methanol, 120 mg of palladium on active carbon (5%) were added, and the mixture was stirred under hydrogen at room temperature for 2 hours. After hydrogen uptake ceased, the catalyst was removed by filtration through celite, and the solvent was stripped off in a rotary evaporator.

Yield: 1.0 g≐98%

1H-NMR (360 MHz, in CDCl₃, data in ppm): 1.35 (s, 9H); 3.3 (s, 3H); 6.3 (s, 1H); 6.8 (s, 1H); 7.15-7.45 (m, 10H)

The compounds listed in Table 1 can be prepared in a similar way.

EXAMPLE 8

Receptor binding data were measured for the compounds listed below using the binding assay described above.

The results are shown in Table 2.

                  TABLE 2                                                          ______________________________________                                         Receptor binding data (K.sub.i values)                                           Compound          ET.sub.A [μM]                                                                        ET.sub.B [μM]                                  ______________________________________                                         I-1             0.038    8                                                       I-91  3.3 >10                                                                  I-166 0.5 4                                                                    I-167 3 >7                                                                   ______________________________________                                     

We claim:
 1. A compound of the formula I ##STR11## where R is a tetrazole, nitrile, or a group ##STR12## where R¹ has the following meanings: b) a succinylimidoxy group;c) a 5-membered heteroaromatic system linked via a nitrogen atom selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl and triazolyl, each of which may be unsubstituted or substituted by one or two halogen atoms or one or two C₁ -C₄ -alkyl or one or two C₁ -C₄ -alkoxy groups; d) R¹ is furthermore a group ##STR13## where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R⁷ isC₁ -C₄ -alkyl, C₃ -C₇ -cycloalkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or unsubstituted or substituted phenyl which can be substituted by one or more of the following radicals:halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, hydroxyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, mercapto, amino, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino; e) R¹ is furthermore a radical OR⁸ where R⁸ is:hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, or a physiologically tolerated organic ammonium ion; C₃ -C₈ -cycloalkyl, a linear or branched C₁ -C₈ -alkyl, CH₂ -phenyl, which may be unsubstituted or substituted by one or more of the following radicals: halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, hydroxyl, C₁ -C₄ -alkoxy, mercapto, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino, a C₃ -C₆ -alkenyl or C₃ -C₆ -alkynyl group, it being possible for this group in turn to carry one to five halogen atoms; R⁸ can furthermore be a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, hydroxyl, C₁ -C₄ -alkoxy, mercapto, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino; a 5-membered heteroaromatic system which is linked via a nitrogen atom and contains one to three nitrogen atoms and which can carry one or two halogen atoms and/or one or two of the following radicals: C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, phenyl, C₁ -C₄ -haloalkoxy and/or C₁ -C₄ -alkylthio; f) R¹ is furthermore a radical ##STR14## where R⁹ is: C₁ -C₄ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₈ -cycloalkyl, it being possible for these radicals to carry a C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio and/or a phenyl radical; phenyl, unsubstituted or substituted; g) R¹ can furthermore be a radical ##STR15## where R⁹ has the abovementioned meaning; h) R¹ can furthermore be ##STR16## where R¹⁰ and R¹¹ can be identical or different and have the following meanings:hydrogen, C₁ -C₇ -alkyl, C₃ -C₇ -cycloalkyl, C₃ -C₇ -alkenyl, C₃ -C₇ -alkynyl, benzyl, phenyl, unsubstituted or substituted, as described above, or R¹⁰ and R¹¹ together form a C₄ -C₇ -alkylene chain which is closed to form a ring, is unsubstituted or substituted by C₁ -C₄ -alkyl, and may contain an oxygen, sulfur or nitrogen atom;the other substituents have the following meanings: R² is hydrogen, hydroxyl, NH₂, NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio, or CR² is linked to CR¹² as indicated below to form a 5- or 6-membered ring; X is nitrogen or CR¹² where R¹² is hydrogen or C₁₋₅ -alkyl, or CR¹² forms together with CR² or CR³ a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C₁₋₄ -alkyl groups and in which in each case one methylene group can be replaced by oxygen, sulfur, --NH or --NC₁₋₄ -alkyl; Y is nitrogen or methine; R³ is hydrogen, hydroxyl, NH₂, NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, --NH--O--C₁₋₄ -alkyl, C₁ -C₄ -alkylthio; or CR³ is linked to CR¹² as indicated above to form a 5- or 6-membered ring; R⁴ and R⁵ (which can be identical or different) are:phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino or C₁ -C₄ -dialkylamino; or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂ --, NH-- or N-alkyl group, or C₃ -C₇ -cycloalkyl; R⁶ is hydrogen, C₁ -C₈ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl or C₃ -C₈ -cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C₁ -C₄ -alkoxy, C₃ -C₆ -alkenyloxy, C₃ -C₆ -alkynyloxy, C₁ -C₄ -alkylthio, C₁ -C₄ -haloalkoxy, C₁ -C₄ -alkylcarbonyl, C₁ -C₄ -alkoxycarbonyl,C₃₋₈ -alkylcarbonylalkyl, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino, phenyl or phenoxy or phenyl, substituted one or more times by halogen, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy or C₁ -C₄ -alkylthio; phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkoxy, phenoxy, C₁ -C₄ -alkylthio, C₁ -C₄ -alkylamino, C₁ -C₄ -dialkylamino, dioxomethylene or dioxoethylene; Z is sulfur or oxygen.
 2. A compound as claimed in claim 1, wherein R is ##STR17## where R¹ is --OR⁸, wherein R⁸ is hydrogen.
 3. A carboxylic acid derivative as claimed in claim 1, wherein at least one of the radicals R⁴ and R⁵ is phenyl.
 4. A carboxylic acid derivative as claimed in claim 3, wherein R⁴ and R⁵ are both phenyl.
 5. A carboxylic acid derivative as claimed in claim 3, wherein R⁶ is C₁ -C₈ -alkyl, unsubstituted or substituted by OH or C₁ -C₄ -alkoxy, and Z is O.
 6. A carboxylic acid derivative as claimed in claim 1, wherein X is CH.
 7. A carboxylic acid derivative as claimed in claim 1 wherein at least one of the radicals X, Y is nitrogen (N).
 8. A carboxylic acid derivative as claimed in claim 1, wherein at least one of the radicals R², R³ is C₁ -C₄ -alkyl.
 9. A method for treating hypertension, pulmonary hypertension, acute and chronic kidney failure, chronic heart failure, cerebral ischemia, restenosis after angioplasty, or prostate cancer comprising administering to a patient in need thereof an therapeutically effective amount of a compound as claimed in claim
 1. 10. A composition containing a combination of a compound as claimed in claim 1 with an inhibitor of the renin-angiotensin system (RAS). 